The "Amyloid Cascade Hypothesis" positing amyloid-ft (Aft) as a fundamental driving mechanism in disease pathogenesis is supported by numerous cellular, animal and human studies. However, an "Alternate Amyloid Hypothesis", positing Aft as an antioxidant that occurs secondary to oxidative stress, is an equally valid explanation for the wealth of in vitro and in vivo findings related to Aft. That the "Alternate Amyloid Hypothesis" and the "Amyloid Cascade Hypothesis" are essentially unchallenged by any currently available data is troubling from a scientific perspective and more so from a clinical perspective where current therapeutic efforts are targeted at the removal or limiting of Aft from the brain. The goal of our proposal is to conduct a series of experiments that should critically test both hypotheses to determine the role of Aft as pathogen or protectant. Specifically, we propose to use inducible transfected cell cultures together with state of the art molecular techniques to test the predominant hypothesis in the field. Our Specific Aims, guided by novel preliminary data are as follows: Aim 1) Determine whether pharmacologic inhibition of Aft with BACE inhibitors affects susceptibility to oxidative stress and whether this effect can be reversed ("rescued") by transfection with Aft1-40, Aft1-42, or C99; Aim 2) Determine whether mutations associated with familial Alzheimer disease are associated with alterations in oxidative stress and whether alterations in Aft production are affected by antioxidants or, vice versa, whether oxidative stress is altered by inhibition of Aft; Aim 3) Determine whether Aft is regulated by intracellular redox balance. Completion of the proposed studies will help determine the role of Aft and, more importantly, guide future therapeutic targets. [unreadable] [unreadable]